N-acyl-N-napthoylglycines as aldose reductase inhibitors

ABSTRACT

Disclosed herein are N-acyl-N-napthoylglycines and methods of their preparation. The N-acyl-N-napthoylglycines are novel aldose reductase inhibitors useful for the treatment or prevention of diabetic complications.

BACKGROUND OF THE INVENTION

This invention relates to N-acyl-N-naphthoylglycines, to the processesfor their preparation, to methods for using the compounds, and topharmaceutical preparations thereof. The compounds have pharmaceuticalproperties which render them beneficial for the treatment of diabetesmellitus and associated conditions.

For many years diabetes mellitus has been treated with two establishedtypes of drugs, namely insulin and oral hypoglycemic agents. These drugshave benefited hundreds of thousands of diabetics by improving theirwell-being and prolonging their lives. However, the resulting longevityof diabetic patients has led to complications such as neuropathy,nephropathy, retinopathy, cataracts and atherosclerosis. Thesecomplications have been linked to the undesirable accumulation ofsorbitol in diabetic tissue, which in turn resulted from the high levelsof glucose characteristic of the diabetic patient.

In mammals, including humans, the key enzyme involved in the conversionof hexoses to polyols (e.g. the sorbitol pathway) is aldose reductase.J. H. Kinoshita and collaborators, see J. H. Kinoshita et al, Biochem.Biophys. Acta, 158,472 (1968) and references cited therein, havedemonstrated that aldose reductase plays a central role in the etiologyof galactosemic cataracts by effecting the conversion of galatose todulcitol (galactitol) and that an agent capable of inhibiting aldosereductase can prevent the detrimental accumulation of dulcitol in thelens. Furthermore, a relationship between elevated levels of glucose andan undesireable accumulation of sorbitol has been demonstrated in thelens, peripheral nervous cord and kidney of diabetic animals, see A.Pirie and R. van Heyningen, Exp. Eye Res., 3,124 (1964); L. T. Chylackand J. H. Kinoshita, Invest. Ophthal., 8,401 (1969) and J. D. Ward andR. W. R. Baker, Diabetol., 6,531 (1970).

K. Sestanj et al, U.S. Pat. No. 4,568,693, Feb. 4, 1986, disclosesN-naphthoylglycine derivatives having aldose reductase activity. Thecompounds of the present invention have an acyl substituent on theglycine nitrogen. Still other related compounds having a similar utilityare N-naphthoylglycine derivatives of K. Sestanj et al, U.S. Pat. No.4,439,617, Mar. 27, 1984; N-(naphthalenylthioxomethyl)amino acidderivatives of K. Sestanj et al, U.S. Pat. No. 4,391,816, July 5, 1983;N-[2-naphthalenyl)thioxomethyl]glycine derivatives of K. Sestanj, U.S.Pat. No. 4,447,452, May 8, 1984; and N-[[6-(loweralkoxy)-5-(trifluoromethylthio)-1-napthalenyl]thioxomethyl]-N-(loweraklyl)glycines of F. Bellini et al, U.S. Pat. No. 4,391,825, July 5,1983. Accordingly, these compounds represent an important new approachfor the treatment of diabetes mellitus.

Y. Mitin et al, Izv. Akad. Nauk SSSR, Ser. Khim. 11, 2666 (1968) (C.A.70:68721 m) discloses N,N-dibenzoylglycine as a chemical intermediatewithout disclosing any biological activity.

A. J. Bates et al, Helv. Chim. Acta, 58, (3) 688 (1975) discloses N,N¹-bis(benzyloxycarbonyl)glycylglycine as a chemical intermediate withoutdisclosing any biological activity.

SUMMARY OF THE INVENTION

The N-acyl-N-naphthoylglycines of this invention are represented byformula (I) ##STR1## wherein R is hydrogen, lower alkyl containing 1 to3 carbon atoms, lower alkoxy containing 1 to 6 carbon atoms,trifluoroethoxy, phenyl, benzyloxy, substituted benzyloxy, or lowerdialkylamino containing 1 to 3 carbon atoms; R¹ is hydrogen or loweralkoxy containing 1 to 3 carbon atoms; R² is halogen or lowerperfluoroalkyl containing 1 to 3 carbon atoms; X is oxygen or sulfur,and the pharmaceutically acceptable salts thereof.

Preferred compounds of the present invention are represented by formula(II) ##STR2## wherein R is hydrogen, lower alkyl containing 1 to 3carbon atoms, lower alkoxy containing 1 to 6 carbon atoms,trifluoroethoxy, phenyl, benzyloxy, substituted benzyloxy, or lowerdialkylamino containing 1 to 3 carbon atoms; R¹ is hydrogen or loweralkoxy containing 1 to 3 carbon atoms; R² is halogen or lowerperfluoroalkyl containing 1 to 3 carbon atoms, and the pharmaceuticallyacceptable salts thereof.

Still further preferred compounds of the present invention arerepresented by formula (III) ##STR3## wherein R is hydrogen or alkoxywherein alkoxy contains 1 to 6 carbon atoms, and the pharmaceuticallyacceptable salts thereof.

The most preferred compounds of the present invention are designated:

N-(ethoxycarbonyl)-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine;

N-(methoxycarbonyl)-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine;and

N-formyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine;and the pharmaceutically acceptable salts thereof.

Also included in the present invention are the chemical intermediatecompounds of formula (VII) ##STR4## wherein R, R¹, and R² are as definedabove.

The N-acyl-N-naphthoylglycines of the present invention can be preparedby the processes described hereinafter.

A method is provided for preventing or relieving diabetes mellitusassociated complications in a diabetic mammal by administering to saidmammal a prophylactic or alleviating amount of a compound of formulas(I), (II), or (III). Such complications include neuropathy, nephropathy,retinopathy and cataracts.

The compounds of formulas (I), (II), (III), when admixed with apharmaceutically acceptable carrier, form a pharmaceutical compositionwhich can be used according to the preceding method.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention, represented by formulas (I), (II), and(III), can exist in rotameric forms. More explicitly, mesomerism impartsa partial double bond character to the carbonyl-nitrogen bonds. Thispartial double bond character leads to restricted rotation about thecarbonyl-nitrogen bonds giving rise to cis and trans rotamers, therestricted rotation being augmented by the bulkiness of neighboringgroups. The rotameric forms represented by structural formulas (I¹),(I²), (I³), and (I⁴) are included within the scope of this invention:##STR5## wherein R, R¹, R², and X are as defined above.

For brevity, the compounds of this invention, including their rotamericforms, are referred to herein as compounds of formula (I), (II), and(III).

The compounds of formula (I) form salts with suitable therapeuticallyacceptable inorganic and organic bases. These derived salts possess thesame activity as their parent acid and are included within the scope ofthis invention. The acid is transformed in excellent yield into thecorresponding therapeutically acceptable salt by neutralization of saidacid with the appropriate inorganic or organic base. The salts areadministered usually in the same manner as the parent acid compounds.Suitable inorganic bases to form these salts include, for example, thehydroxides, carbonates or bicarbonates of the therapeutically acceptablealkali metals of alkaline earth metals, for example, sodium, potassium,magnesium, calcium and the like. Suitable organic bases include thefollowing amines: benzylamine; lower mono-, di- and trialkylamines, thealkyl radicals of which contain up to three carbon atoms, such asmethylamine, dimethylamine, trimethylamine, ethylamine, di- andtriethylamine, methylethylamine, and the like; mono-, di- andtrialkanolamines, the alkanol radicals of which contain up to threecarbon atoms, for example, mono-, di- and triethanolamine;alkylene-diamines which contain up to six carbon atoms, such ashexamethylenediamine; cyclic saturated or unsaturated bases containingup to six carbon atoms, such as pyrrolidine, piperidine, morpholine,piperazine and their N-alkyl and N-hydroxyalkyl derivatives, such asN-methyl-morpholine and N-(2-hydroxyethyl)-piperidine, as well aspyridine. Furthermore, there may be mentioned the correspondingquaternary salts, such as the tetraalkyl (for example tetramethyl),alkyl-alkanol (for example methyl-triethanol and trimethyl-monoethanol)and cyclic ammonium salts, for example the N-methylpyridinium,N-methyl-N-(2-hydroxyethyl)morpholinium, N,N-dimethylmorpholinium,N-methyl-N-(2-hydroxyethyl)morpholinium, N,N-dimethylpiperidinium salts,which are characterized by having good water-solubility. In principle,however, there can be used all the ammonium salts which arephysiologically compatible.

The transformations to the salts can be carried out by a variety ofmethods known in the art. For example, in the case of the inorganicsalts, it is preferred to dissolve the acid of formula (I) in watercontaining at least one equivalent amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. Advantageously,the reaction is performed in a water-miscible, inert organic solvent,for example, methanol, ethanol, dioxane, and the like in the presence ofwater. For example, such use of sodium hydroxide, sodium carbonate orsodium bicarbonate gives a solution of the sodium salt. Evaporation ofthe solution or addition or a water-miscible solvent of a more moderatepolarity, for example, a lower alkanol, for instance, butanol, or alower alkanone, for instance, ethyl methyl ketone, gives the solidinorganic salt if that form is desired.

To produce an amine salt, the acidic compound of formula (I) isdissolved in a suitable solvent of either moderate or low polarity, forexample, ethanol, methanol, ethyl acetate, diethyl ether and benzene. Atleast an equivalent amount of the amine corresponding to the desiredcation is then added to that solution. If the resulting salt does notprecipitate, it can usually be obtained in solid form by addition of amiscible diluent of lower polarity, for example, benzene or petroleumether, or by evaporation. If the amine is relatively volatile, anyexcess can easily be removed by evaporation. It is preferred to usesubstantially equivalent amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe acid of formula (I) with an equivalent amount of the correspondingquaternary ammonium hydroxide in water solution, followed by evaporationof the water.

The N-acyl-N-naphthoylglycines of this invention may be administered tomammals, for example, man, monkeys or dogs, either alone or in dosageforms, i.e., capsules or tablets, combined with pharmacologicallyacceptable excipients.

Advantageously the compounds of this invention may be given orally.However, the method of administering the present active ingredients ofthis invention is not be construed as limited to a particular mode ofadministration. For example, the compounds may be administered topicallydirectly to the eye in the form of drops of sterile, buffered ophthalmicsolutions, preferably of pH 7.2-7.6. Also, they may be administeredorally in solid form containing such excipients as starch, milk sugar,certain types of clay and so forth. They may also be administered orallyin the form of solutions or they may be injected parenterally. Forparenteral administration they may be used in the form of a sterilesolution, preferably of pH 7.2-7.6, containing a pharmaceuticallyacceptable buffer.

The dosage of the N-acyl-N-naphthoylglycines will vary with the form ofadministration. Furthermore, it will vary with the particular host undertreatment. Generally, treatment is initiated with small dosagessubstantially less than the optimal dose of the compound. In general,the compounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects. For topicaladministration, a 0.05-1.8% solution may be administered dropwise in theeye. The frequency of instillation varies with the subject undertreatment from a drop every two or three days to once daily. For oral orparenteral administration a preferred level of dosage ranges from about0.5 mg to about 1000 mg per kilo of body weight per day, althoughaforementioned variations will occur. However, a dosage level that is inthe range of from about 5.0 mg to about 60 mg per kilo of body weightper day is most satisfactory.

Unit dosage forms such as capsules, tablets, pills and the like maycontain from about 25 mg to about 1250 mg of the active ingredients ofthis invention with a pharmaceutical carrier. Thus, for oraladministration, capsules can contain from between about 25 mg to about1250 mg of the active ingredients of this invention with or without apharmaceutical diluent. Tablets, either effervescent or noneffervescent,can contain between about 25 to 1250 mg of the active ingredients ofthis invention together with conventional pharmaceutical carriers. Thus,tablets, which may be coated and either effervescent or noneffervescent,may be prepared according to the known art. Inert diluents or carriers,for example, magnesium carbonate or lactose, can be used together withconventional disintegrating agents for example, magnesium stearate.

The N-acyl-N-naphthoylglycines can also be used in combination withinsulin or oral hypoglycemic agents to produce a beneficial effect inthe treatment of diabetes mellitus. In this instance, commerciallyavailable insulin preparations or oral hypoglycemic agents, exemplifiedby acetohexamide, chlorpropamide, tolazamide, tolbutamide andphenformin, are suitable. The compounds hereof can be administeredsequentially or simultaneously with insulin or the oral hypoglycemicagent. Suitable methods of administration, compositions and doses of theinsulin preparation or oral hypoglycemic agent are described in medicaltextbooks; for instance, "Physicians' Desk Reference", 36 ed., MedicalEconomics Co., Oradell, N.J. U.S.A., 1982. When used in combination, theN-acyl-N-naphthoylglycines are administered as described previously. TheN-acyl-N-naphthoylglycines can be administered with the oralhypoglycemic agent in the form of a pharmaceutical compositioncomprising effective amounts of each agent.

The aldose reductase inhibiting property of the compounds of thisinvention and the utilization of the compounds in preventing,diminishing and alleviating diabetic complications are demonstrable inexperiments using galactosemic rats, see Dvornik et al, Science, 182,1146 (1973). Such experiments are exemplified hereinbelow after thelisting of the following general comments pertaining to theseexperiments.

(a) Four or more groups of six male rats, 50-70 g, Sprague-Dawleystrain, were used. The first group, the control group, was fed a mixtureof laboratory chow (rodent Laboratory Chow, Purina) and glucose at 20%(w/w %) concentration. The untreated galactosemic group and thedrug-treated groups were fed a similar diet in which galactose issubstituted for glucose. The test compound was either admixed to thediet or administered by gavage. In experiments involving compoundadministration in the diet, the average dose administered was calculatedfrom the actual food intake of the animals in each group. Theconcentration of galactose in the diet of the treated groups was thesame as that for the untreated galactosemic group.

(b) After four days, the animals were killed by decapitation. Theeyeballs were removed and punctured with a razor blade; the freed lenseswere rolled gently on filter paper and weighed. The sciatic nerves weredissected as completely as possible and weighed. Both tissues whenfrozen can be kept up to two weeks before being analyzed for galactitol.

(c) The polyol determination was performed by a modification of theprocedure of M. Kraml and L. Cosyns, Clin. Biochem., 2,373 (1969). Onlytwo minor reagent changes were made: (a) The rinsing mixture was anaqueous 5% (w/v) trichloroacetic acid solution and (b) the stocksolution was prepared by dissolving 25 mg of dulcitol in 100 mL of anaqueous trichloroacetic acid solution. [N.B.: For each experiment theaverage value found in the tissue from rats fed the glucose diet wassubtracted from the individual values found in the corresponding tissuein galactose-fed rats to obtain the amount of polyol accumulated.] Thealdose reductase inhibiting effects of the compounds of formula (I) werealso tested by employing an in vitro testing procedure similar to thatdescribed by S. Hayman and J. H. Kinoshita, J. Biol. Chem., 240,877(1965). In the present case the procedure of Hayman and Kinoshita wasmodified in that the final chromatography step was omitted in thepreparation of the enzyme from bovine lens.

The following tabulated results show that the N-acyl-N-naphthoylglycinesof this invention show the property that they diminish the accumulationof galactitol in the lenses and sciatic nerves of rats fed galactose.The figures under L, N, and D represent the percentage decrease ofgalactitol accumulation in the tissues of the lens, sciatic nerve, anddiaphragm, respectively, for treated rats as compared to untreated rats.

Examination of the results tabulated below show that theN-acyl-N-naphthoylglycines of this invention are well suited as aldosereductase inhibitors. For example,N-(ethoxycarbonyl)-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycineat a dose of 57 mg/kg/day andN-(methoxycarbonyl)-N-[[6-methoxy-5-(trifluoromethyl)-1-napthalenyl]carbonyl]glycineat a dose of 48 mg/kg/day give comparable results toN-[[6-methoxy-5-(trifluoromethyl)-1-napthalenyl]thioxomethyl]-N-methyglycineat 9 mg/kg/day. The latter compound, is also known as tolrestat.

    __________________________________________________________________________                                  % Lowering dulcitol                                               % Inhibition                                                                              accumulation    Synthetic                                         IN VITRO    IN VIVO         Process                         Ex.                                                                              R              10.sup.-5 M                                                                       10.sup.-6 M                                                                       10.sup.-7 M                                                                       mg/kg                                                                             (%)L                                                                              (%)N                                                                              (%)D                                                                              (Scheme)                                                                           m.p.                       __________________________________________________________________________                                                       °C.                  ##STR6##                                              (III)                  1  OCH.sub.2CH.sub.3                                                                            97  94  47   97 12  90  83  2    86-88.5                                                   57 19  56  70                                  2  OCH.sub.3      98  97  82   48 N.S.                                                                              70  54  1    148-150                    3  OCH.sub.2CH.sub.2CH.sub.3                                                                    95  90  81   48 N.S.                                                                              N.S.                                                                              N.S.                                                                              1    101-102                                      48% (4 × 10.sup.-8 M)                                 4  OCH(CH.sub.3).sub.2                                                                          96  86  35  N.S.                                                                              N.S.                                                                              N.S.                                                                              N.S.                                                                              1    138-140                    5  OCH.sub.2C(CH.sub.3).sub.3                                                                   90  64  18  105 N.S.                                                                              N.S.                                                                              N.S.                                                                              1    118-120                        ##STR7##      95  89  66   67 N.S.                                                                              N.S.                                                                              N.S.                                                                              1    158-160                    7                                                                                 ##STR8##      95  89  49  107 N.S.                                                                              N.S.                                                                              N.S.                                                                              1    187-189                    8  H              95  96  89  107 13  51  82  3    142-144                    9  CH.sub.3       96  91  61  100 N.S.                                                                              36  39  3    141-142                    10                                                                                ##STR9##      90  62  15   50 N.S.                                                                              N.S.                                                                              N.S.                                                                              4    143-145(dec.)              11 N(CH.sub.3).sub.2                                                                            22   3  N.S.                                                                              N.D.                                                                              --  --  --  5    145-147                     ##STR10##                                                                    12 OCH.sub.3      85  54  10  102 N.S.                                                                               N.S. 24                                                                              1    119-121                    13                                                                                ##STR11##     87  57  12  N.D.                                                                              --  --    --                                                                              1    135-137                    14 H              90  73  22  104 N.S.                                                                              N.S   17                                                                              3    167-169                    15 CH.sub.3       82  41   7  112 N.S.                                                                              N.S.  N.S.                                                                            3    124-127                    16                                                                                ##STR12##     83  58  10  111 N.S.                                                                              N.S.  N.S.                                                                            4    160-162(dec.)              17 N(CH.sub.3).sub.2                                                                            23   4  N.S.                                                                              N.D.                                                                              --  --    --                                                                              5    138-139                     ##STR13##                                                                    18a                                                                              COOCH.sub.3    94  88  29   51 N.S.                                                                              N.S.                                                                              80  6    160                        18b                                                                              CH.sub.3 (tolrestat)                                                                         98  94  65   9  N.S.                                                                              58  87                                  __________________________________________________________________________     N.S. = not significant                                                        N.D. = not determined                                                         L = lens                                                                      N = nerve                                                                     D = diaphragm                                                            

The Process

The N-acyl-N-naphthoylglycines can be prepared by the following reactionschemes: ##STR14## wherein R, R¹, and R² are as defined above.

Referring to the General Scheme, the carboxylic acid (IV), obtained bythe process of U.S. Pat. No. 4,568,693 or W. F. Short et al, J. Chem.Soc. 990 (1950), is converted to the corresponding carboxylic acidchloride (V) by reaction with thionyl chloride (1 to 5 eq) in a solventsuch as dichloromethane, acetonitrile, chloroform, benzene, or toluene,or thionyl chloride can be used as solvent. A catalytic amount ofdimethylformamide is used (0.01 to 0.03 eq). A reaction temperatureranging from 20° C. to 110° C. is used for reaction times ranging from10 minutes to 3 hours. Other reagents that can be used under similarconditions are phosphorus trichloride and oxalyl chloride.

The carboxylic acid chloride (V) is converted to the correspondingcarboxylic acid amide (VI) by reaction of a solution of (V) in an inertorganic solvent such as THF, dichloromethane, benzene, or toluene withconcentrated aqueous ammonium hydroxide at temperatures ranging from 0°C. to 25° C. for reaction times ranging from 5 minutes to 1 hour.

The corresponding carboxylic acid amide (VI) can alternatively be formedby reacting (V) with a saturated solution of ammonia gas in an inertsolvent (such as THF) at temperatures ranging from 0° C. to 25° C. forreaction times ranging from 5 minutes to 1 hour.

According to the procedure of Y. Lin et al, Synthesis, 119 (1980) thecarboxylic acid amide (VI) is reacted neat with the appropriateN,N-dimethylcarboxamide dimethylacetal (1 to 5 eq, dimethylformamidedimethylacetal to produce the compounds (VII) wherein R is hydrogen anddimethylacetamide dimethylacetal to produce the compounds (VII) whereinR is methyl) at temperatures of 100° C. to 140° C. for 5 to 25 minutesto produce the appropriate nonisolated amidine. The resulting amidine isadded to 50 to 80% aqueous acetic or formic acid at temperatures rangingfrom 20° C. to 40° C. for 5 to 20 minutes.

Alternatively (VI) is reacted with the appropriate acid anhydride with acatalytic amount of concentrated sulfuric acid (0.05 to 0.2 eq) attemperatures ranging from 80° C. to 120° C. for 30 minutes to 4 hours.For example, reaction of (VI) with 1 to 2 eq acetic anhydride produces(VII) wherein R is methyl.

Reaction of (VI) with a base (sodium hydride, potassium hydride, lithiumdiisopropylamide, 1.0 to 1.5 eq) is anhydrous THF at temperaturesranging from 0° C. to 30° C. for 20 minutes to 1 hour, and then reactionwith N,N-dimethylcarbamoyl chloride (1.0 to 1.2 eq) at temperaturesranging from 20° C. to 65° C. for 1 to 4 hours produces compound (VII)wherein R is --N(CH₃)₂.

According to the procedure of C. L. Arcus et al, J. Chem. Soc., 4018(1954) and 1091 (1957), reaction of (V) with silvercyanate (1 to 2 eq)in an inert organic solvent such as carbon tetrachloride, chloroform,dichloromethane, or benzene at temperatures ranging from 60° C. to 100°C. for reaction times from 1 hour to 24 hours produces the intermediate,nonisolated isocyanate ##STR15##

This isocyanate is reacted with the appropriate alcohol (1 to 5 eq) attemperatures ranging from 40° C. to 90° C. for times ranging from 1 to 3hours to produce the compounds (VII) wherein R is lower alkoxycontaining 1 to 6 carbon atoms, trifluoroethoxy, benzyloxy, orsubstituted benzyloxy.

Benzamide (1.0 to 1.5 eq) is reacted with a base such as sodium hydride,potassium hydride, lithium diisopropylamide (1.1 to 1.6 eq) in anhydrousTHF at 0° C. to 30° C. for 20 minutes to 1 hour. The acid chloride (V)is then added and reaction at 20° C. to 65° C. for 1 hour to 4 hoursproduces the compounds (VII) wherein R is phenyl.

Reaction of (VII) in THF or DMF with 1.0 to 1.3 eq of a base such assodium hydride, potassium hydride, lithium diisopropylamide (in THF) attemperatures between 20° C. and 60° C. from 10 minutes to 4 hours andthen reaction with tert-butyl bromoacetate or tert-butyl chloroacetate(1.0 to 2.0 eq) at temperatures from 0° C. to 65° C. for a period of 30minutes to 3 days produces the compounds (IX).

Alternatively the carboxylic acid chloride (V) is added to a solution oftert-butyl glycinate (1.0 to 3.0 eq) in an organic solvent such as THFand a base such as triethylamine, potassium carbonate, or sodiumbicarbonate and reacted at a temperature of 0° C. to 80° C. for 2 to 24hours to produce the compounds (VIII).

Reaction of (VIII) with phosphorus pentasulfide (2.0 to 5.0 eq) in aninert solvent toluene or xylene at 80° C. to 150° C. for 20 minutes to 7hours or with Lawesson's reagent (0.6 to 3 eq) in the inert solventtoluene or xylene, at 20° C. to 150° C. for 20 minutes to 16 hoursproduces the compounds (X).

A base, such as solid sodium hydroxide or solid potassium hydroxide (1.0to 2.0 eq), is added to an acetone solution of (VIII) or (X) at -40° C.and stirred for 30 minutes to 1 hour. To this is added an alkylchloroformate such as methyl chloroformate or ethyl chloroformate (1.0to 2.0 eq) and the reaction temperature maintained at 20° C. to 30° C.for 1 hour to 4 hours to produce the compounds (IX) or (XI),respectively.

(IX) or (XI) is reacted with an organic protic acid such astrifluoroacetic acid (1 eq up to use as solvent) or formic acid (5 eq upto use as solvent). The trifluoroacetic acid or formic acid is used asthe solvent or the reaction is carried out in a halocarbon solvent, suchas dichloromethane, chloroform, or carbon tetrachloride at temperaturesfrom 20° C. to 40° C. for periods of 1 hour to 3 hours to produce thecompounds (I, X=O) or (I, X=S), respectively.

Trimethylsilyliodide (1 to 10 eq) in a halocarbon solvent attemperatures from 20° C. to 40° C. for periods of 1 to 3 hours was alsoused to remove the protective group and produce the compounds (I, X=O)or (I, X=S), respectively.

Preferably, the compounds of the present invention are producedaccording to the following Schemes: ##STR16## wherein R is alkoxy,aralkoxy, or aryloxy; R¹ and R² are as defined above. ##STR17##

The following Examples further illustrate this invention.

EXAMPLE 1N-[[6-Methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-[(ethoxy)carbonyl]glycine[(I):R=OC₂ H₅ ; R¹ =OCH₃ ; R² =CF₃ ; X=O] Step 1. Preparation ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,1,1-dimethylethylester

According to the procedure of C. L. Arcus et al, J. Chem. Soc., 1954,4018; J. Chem. Soc., 1957, 1091, dimethylformamide (1.0 mL) was added toa solution of 5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylicacid, prepared by the process of U.S. Pat. No. 4,568,693 (10.0 g, 37.0mmol) in thionyl chloride (200 mL) at 20° C. The mixture was refluxedfor 4 hours, cooled, solvent evaporated and the residual volatilespurged with benzene. The residual acid chloride was added to a solutionof tert-butyl glycinate (8.0 mL) in anhydrous tetrahydrofuran (300 mL),followed by triethylamine (10.0 mL, 136 mmol). The resultant solutionwas stirred at 20° C. for 24 hours. The solvent was evaporated, theresidual oil extracted with ether (500 mL), washed with water (300 mL),saturated sodium bicarbonate (300 mL), and brine (300 mL), dried(MgSO₄), filtered, and evaporated to give an oil, which waschromatographed in 15% ethyl acetatehexanes to yield the product (10.1g, 71.6%), m.p. 104°-106° C.

NMR (DMSO-d₆): δ 9.0 (s, 1H, NH), 8.58 (d, 1H, ArH), 8.18 (d, 1H, ArH),7.60-7.80 (m, 3H, ArH), 4.0 (s, 3H, OCH₃), 3.95 (d, 2H, NCH₂), 1.42 (s,9H, C(CH₃)₃)

IR (KBr, cm⁻¹): 3310 (N--H), 3000 (C--H), 1760 (C═O), 1740 (C═O, 1620,1600 (C═C);

Calcd.: C, 59.50; H, 5.25; N, 3.60%.

Found: C, 58.92: H, 5.48; N, 4.02%.

Step 2. Preparation ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N-[(ethoxy)carbonyl]glycine,1,1-dimethylethylester

According to the procedure of W. Walter et al, Phosphorus Sulfur Relat.Elem., 25(1) 63 (1985) solid sodium hydroxide (powered, 0.87 g, 21.8mmol) was added to a solution ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,1,1-dimethylethyl ester (5.0 g, 13.0 mmol) in dry acetone (200 mL) at-40° C. then stirred for 30 minutes at -40° C. Ethyl chloroformate (1.5mL, 15.7 mmol) was added, and the solution allowed to warm to 20° C.over 2 hours. The acetone was evaporated under reduced pressure, water(300 mL) was added, and the precipitated yellow solid was filtered,washed with water (200 mL) and petroleum ether (2×50 mL) then dried at60° C./0.1 m.m. Hg to yield the pure product (3.1 g, 55.3%), m.p.105°-106° C.

NMR (CDCl₃): δ 8.30 (d, 1H, ArH), 7.40-7.60 (m, 4H, ArH), 5.10 (s, 2H,NCH₂), 4.0 (s, 3H, OCH₃), 3.80 (q, 2H, CH₂ CH₃), 1.50 (s, 9H, C(CH₃)₃),0.60 (t, 3H, CH₂ CH₃).

IR (KBr, cm⁻¹): 3000 (C--H), 1770, 1740, 1650 (C═O), 1610, 1590 (C═C);

Calcd: C, 58.02; H, 5.31: N, 3.07%.

Found: C, 58.10; H, 5.09; N, 3.06%.

Step 3. Preparation ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-[(ethoxy)carbonyl]glycine

TheN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-[(ethoxy)carbonyl]glycine,1,1-dimethylethyl ester (2.5 g, 5.5 mmol) was stirred at 20° C. informic acid (30 mL), for 6 hours. Water (400 mL) was added, and themixture was extracted with ether (300 mL). The ether layer was washedwith water (100 mL) then back-extracted with saturated sodiumbicarbonate (250 mL). The aqueous layer was separated and poured into 2normal hydrochloric acid (80 mL), the aqueous solution was extractedwith ether (300 mL), washed with brine (200 mL), filtered, andevaporated to yield a white syrup, which crystallized on triturationwith methylene chloride-hexanes to yield the pure product (1.0 g, 35%),m.p. 86°-88.5° C.

NMR (CDCl₃): δ 8.35 (d, 1H, ArH), 8.15 (d, 1H, ArH), 7.35-7.55 (m, 3H,ArH), 4.85 (s, 2H, NCH₂), 4.0 (s, 3H, OCH₃), 3.95 (q, 2H, CH₂ CH₃), 0.65(t, 3H, CH₂ CH₃).

IR (KBr, cm⁻¹): 3400-3000 (COOH, broad), 1760, 1740, 1700 (C═O), 1620,1590 (C═C) (C-H);

Calcd.: C, 54.14; H, 4.04; N, 3.51%.

Found: C, 54.70; H, 4.30; N, 3.39%.

EXAMPLE 2N-[[6-Methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-[(methoxy)carbonyl]glycine[(I): R=OCH₃ ; R¹ =OCH₃ ; R² =CF₃ ; X=O]

Step 1. Preparation ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid,methyl ester

Dimethylformamide (1.0 mL, anhydrous) was added to a solution of6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid (10.0 g, 37.0mmol) in thionyl chloride (100 mL), then refluxed for 1 hour. Thesolution was cooled and the solvent was evaporated. The solvent wasreplaced with benzene (100 mL) and re-evaporated to yield the acidchloride which was stirred in carbon tetrachloride (250 mL), and addedto a suspension of silver cyanate (5.5 g, 37.0 mmol) in carbontetrachloride (100 mL). The resultant mixture was refluxed for 16 hours,cooled to room temperature and the solvent was evaporated. The residuewas stirred in benzene (250 mL) and a solution of methanol (25 mL, 0.616mol) in benzene (100 mL) was added to it. This was stirred at 70° C. for3 hours then filtered while hot. The filtrate was allowed to cool andcrystallize. The crystals were then collected by suction filtration,washed with hexane and dried under vacuo to give the white solid product(1.3 g, 11%), m.p. 188°-190° C.

NMR (DMSO-d₆): δ 10.2 (s, 1H, N--H), 8.20 (d, 1H, ArH), 8.10 (d, 1H,ArH), 7.70 (m, 2H, ArH), 7.46 (d, 1H, ArH), 4.0 (s, 3H, OCH₃), 3.40 (s,3H, COOCH₃).

IR (KBr, cm⁻¹): 3400, 3200 (N--H), 1770, 1690 (C═O), 1615, 1600 (C═C)

Calcd.: C, 55.05; H, 3.70; N, 4.28%.

Found: C, 55.78; H, 3.98; N, 5.18%.

Step 2. Preparation ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-[(methoxy)carbonyl]glycine,1,1-dimethylethyl ester

N-[[6-Methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid,methyl ester (2.2 g, 6.72 mmol) was added to a suspension of sodiumhydride (60% in oil, 0.29 g, 7.25 mmol) in tetrahydrofuran (anhydrous,150 mL) and the mixture stirred for 1.5 hours at 20° C. tert-Butylbromoacetate (1.20 mL, 7.40 mmol) was added and the resultant solutionwas stirred for 20 hours at 20° C. The solvent was evaporated and theresidual solid triturated with hexanes (3×20 mL), to yield the pureproduct (2.1 g, 71.2%) as a white crystalline solid.

NMR (DMSO): δ 8.20 (d, 1H, ArH), 8.10 (d, 1H, ArH), 7.64-7.70 (m, 2H,ArH), 7.40-7.60 (d, 1H, ArH), 4.60 (s, 2H, NCH₂), 4.0 (s, 3H, OCH₃, 3.42(s, 3H, OCH₃), 1.42 (s, 9H, C(CH₃)₃).

IR (KBr, cm⁻¹): 3000 (C--H), 1770 (C═O), 1750 (C═O), 1690 (C═O), 1620,1600 (C═C);

Calcd.: C, 57.40; H, 4.59; N, 3.19%.

Found: C, 56.68; H, 5.52; N, 4.67%.

Step 3. Preparation ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-[(methoxy)carbonyl]glycine

Trifluoroacetic acid (20.0 mL, 260 mmol) was added to a solution ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine,1,1-dimethylethyl ester (1.5 g, 3.41 mmol) in chloroform (25 mL) at 20°C. and the mixture refluxed for 1.5 hours. The solution was cooled to20° C. and the solvent evaporated under reduced pressure. The residualsolid was recrystallized from acetone-water and dried at 70° C./0.1 m.m.Hg to yield the pure product as a white solid (1.4 g, 100%), m.p.148°-150° C.

NMR (DMSO): δ 9.82 (s, 1H, COOH), 8.20 (d, 1H, ArH), 8.10 (d, 1H, ArH),7.64-7.70 (m, 2H, ArH), 7.50 (d, 1H, ArH), 4.60 (s, 2H, NCH₂), 4.05 (s,3H, OCH₃), 3.42 (s, 3H, COOCH₃).

IR (KBr, cm⁻¹): 3300-3000 (COOH), 1775 (C═O), 1730, 1700 (C═O), 1620(C═C);

Calcd.: C, 52.99; H, 3.66; N, 3.63%.

Found: C, 52.80; H, 3.47; N, 3.55%.

EXAMPLE 8N-Fromyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine[(I): R=H; R¹ =OCH₃ ; R² =CF₃ ; X=O] Step 1. Preparation of6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide

Dimethylformamide (0.05 mL) was added to a stirred suspension of5-(trifluoromethyl)-6-methoxy-1-napthalenecarboxylic acid (14.84 g,54.32 mmol) in thionyl chloride (30 mL). A reflux condenser and CaCl₂drying tube were attached to the apparatus and the reaction mixture washeated to 50°-60° C. Dissolution occurred within 10 minutes. After 20minutes the reaction mixture was cooled to room temperature, and theexcess SOCl₂ was removed. The residual solid was dissolved in dry THF(100 mL) and added dropwise over a 10-15 minute period to a cold (0°-10°C.) mechanically stirred solution of concentrated ammonium hydroxide(400 mL). After an additional 10 minutes, water (300 mL) was added andthe reaction mixture was filtered. The white solid was washed with waterand dried in vacuo (14.9 g), m.p. 258° C.

NMR (d⁶ DMSO, 200 MHz): δ 4.00 (s, 3H, OCH₃), 7.5-7.8 (m, 4H, ArH andNH), 8.0-8.2 (m, 2H, ArH and NH), 8.54 (d, 1H, ArH).

IR (KBr, cm⁻¹): 3360, 3190 (NH), 1660 (C═O).

Calcd.: C, 58.00; H, 3.74; N, 5.20%.

Found: C, 58.31; H, 3.77; N, 5.08%.

Step 2. Preparation ofN-formyl-6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide

A suspension of 6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide(14.99 g, 55.7 mmole) in dimethylformamide dimethylacetal (22.2 mL, 3.0eq) was heated to 120° C. under a dry nitrogen atmosphere for 5 minutes.The resultant solution was cooled to 0° C. in an ice bath where crystalsformed. The crystals were collected by suction filtration then dissolvedin acetic acid (70% by volume aqueous solution, 70 mL). After 5 minutes,a precipitate appeared. The precipitate was collected by suctionfiltration, washed with water (1×40 mL), and dried in vacuo to provide awhite solid (14.95 g, 90%). A portion of this solid (1.5 g) wasrecrystallized in 1:2 hexane:chloroform to provide the product as whiteneedles (0.939 g, 56%), m.p. 187°-189° C.

NMR (d⁶ DMSO, 400 MHz): δ 4.02 (s, 3H, OCH₃), 7.71-7.78 (m, 3H, ArH),8.24 (d, 1H, J=8.2 Hz, ArH), 8.54 (d, 1H, J=9.8 Hz, ArH), 9.26 (d, 1H,J=9.1 Hz, CHO), 11.81 (d, 1H, J=9.1 Hz, NH).

IR (KBr, cm⁻¹): 3300 (NH), 1732 (C═O), 1683 (C═O), 1620 and 1599 (C═C);

Calcd.: C, 56.57; H, 3.39; N, 4.71%.

Found: C, 56.58; H, 3.65; N, 4.65%.

Step 3. Preparation ofN-formyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,1,1-dimethylethyl ester

Sodium hydride (60% by weight dispersion in mineral oil, 2.04 g, 1.10eq) was added to a solution ofN-formyl-6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide (13.80g, 46.4 mmole) in anhydrous dimethylformamide (100 mL) at 0° C. under adry nitrogen atmosphere. The reaction was warmed to room temperature for15 minutes, then recooled to 0° C. t-Butylbromo acetate (7.49 mL, 1.0eq) was added to the reaction mixture. After 65 minutes, moret-butylbromo acetate (1.50 mL, 0.2 eq) was added. After 11/4 hours, thereaction was quenched with saturated aqueous ammonium chloride (100 mL)and warmed to room temperature. The reaction mixture was diluted withwater (1.5 L) and extracted with ether (3×250 mL). The ether extractswere combined, dried with magnesium sulfate, filtered, and the ether wasremoved. The crude product was purified by flash chromatography (17:3petroleum ether:ethyl acetate, silica) to provide the product as whitecrystals (14.53 g, 76 %), m.p. 101°-104° C.

NMR (CDCl₃, 400 MHz): δ 4.02 (s, 3H, OCH₃), 4.59 (s, 2H, CH₂ CO₂), 7.46(d, 1H, J=9.4 Hz, ArH), 7.51 (d, 1H, J=7.0 Hz, ArH), 7.62 (t, 1H, J=7.1Hz, ArH), 8.30 (d, 1H, J=9.4 Hz, ArH), 8.38 (d, 1H, J=8.9 Hz, ArH), 8.65(s, 1H, CHO).

IR (KBr, cm⁻¹): 1758 (C═O), 1730 (C═O), 1618 and 1599 (C═C).

Calcd.: C, 58.39; H, 4.90; N, 3.40%.

Found: C, 58.69; H, 4.88: N, 3.32%.

Step 4. Preparation ofN-formyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine

A solution ofN-formyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,1,1-dimethylethyl ester (12.86 g, 31.3 mmole) in trifluoroacetic acid(100 mL) was stirred at room temperature for 5 minutes. The reaction wasdiluted with water (700 mL) and the resultant precipitate was collectedby suction filtration. The solid was washed with water (2×25 mL) andrecrystallized in 2:1 hexane:chloroform to provide the product as whiteneedles (5.09 g, 46%), m.p. 142°-144° C.

NMR (d⁶ DMSO, 400 MHz): δ 4.02 (s, 3H, OCH₃), 4.53 (s, 2H, NCH₂ CO₂ H),7.65 (d, 1H, J=6.9Hz, ArH), 7.73-7.78 (m, 2H, ArH), 8.24-8.28 (m, 2H,ArH), 8.69 (s, 1H, CHO), 13.26 (broad peak, 1H, CO₂ H).

IR (KBr, cm⁻¹): 3140 (COOH), 1753 (C═O), 1702 (C═O), 1651 (C═O);

Calcd.: C, 54.09; H, 3.40; N, 3.94%.

Found: C, 54.29; H, 3.63; N, 3.83%.

EXAMPLE 10N-Benzoyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine[(I): R=Ph; R¹ =OCH₃ ; R² =CF₃ ; X=O] Step 1. Preparation ofN-benzoyl-N-6-methoxy-5-(trifluoromethyl)-1-napthalenecarboxamide

According to the procedure of J. D. Albright et al, J. Med. Chem., 26,1393 (1983), a solution of benzamide (9.96 g, 1.2 eq) in anhydroustetrahydrofuran (175 mL) was added to a stirred suspension of sodiumhydride (60% by weight dispersion in mineral oil, 3.29 g, 1.2 eq) inanhydrous THF (175 mL) at room temperature under a dry nitrogenatmosphere. After 20 minutes, a solution of5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic acid chloride(˜20.0 g, 68.5 mmole) in anhydrous THF (100 mL) was added slowly to thereaction mixture. [5-(Trifluoromethyl)-6-methoxy-1-naphthalenecarboxylicacid chloride was prepared from5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic acid (18.50 g,68.5 mmole), thionyl chloride (28 mL, 3.5 eq), and dimethylformamide(0.167 mL, 0.03 eq) in anhydrous tetrahydrofuran (56 mL). The solutionwas stirred at room temperature for 45 minutes, then the organic solventwas removed. The acid chloride was used without further purification.]After 50 minutes, the reaction mixture was diluted with water (1.3 L).The aqueous phase was acidified to pH5 with concentrated hydrochloricacid and extracted with ethyl acetate (8×300 mL). The extracts werecombined, dried with magnesium sulfate, and the ethyl acetate removed.The crude product was recrystallized in 1:4 chloroform:acetonitrile toprovide the off white solid (6.96 g, 27%), m.p. 248°-250° C.

NMR (d⁶ DMSO, 200 MHz): δ 4.01 (s, 3H, ArOCH₃), 7.51 (t, 2H, J=7.6 Hz,PhH), 7.59-7.71 (m, 4H, ArH and PhH), 7.94 (d, 2H, J=7.7 Hz, PhH), 8.18(broad d, 1H, ArH), 8.37 (d, 1H, J=10.0 Hz, ArH).

IR (KBr, cm⁻¹): 3220 (NH), 3125 (NH), 2960 (CH), 1703 (C═O), 1672 (C═O),1612 (C═C);

Anal. Calcd.: C, 64.34; H, 3.78; N, 3.75%.

Found: C, 64.18; H, 4.19; N, 4.00%.

Step 2. Preparation ofN-benzoyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,1,1-dimethylethyl ester

Sodium hydride (60% by weight dispersion in mineral oil, 0.818 g, 1.10eq) was added to a stirred suspension ofN-benzoyl-N-6-methoxy-5-(trifluoromethyl)-1-napthalenecarboxamide (6.96g, 18.6 mmole) in anhydrous dimethylformamide (80 mL) at 0° C. under adry nitrogen atmosphere. The reaction mixure was warmed to roomtemperature for 15 minutes, then cooled to 0° C. and t-butylbromoacetate (3.00 mL, 1.0 eq) was added. After another 15 minutes, thereaction was warmed to room temperature. More t-butyl bromoacetate (0.60mL, 0.2 eq) was added after 2 2/3 hours and again 4 1/3 hours totalreaction time. After 22 hours, the reaction mixture was diluted withwater (1.3 L). The aqueous phase was basified to pH 9 with 10% aqueoussodium hydroxide solution. The aqueous phase was extracted with ether(5×300 mL). The ether extracts were combined, washed with saturatedaqueous sodium chloride solution (1×300 mL), dried with magnesiumsulfate, and the ether was removed. The crude product was flashchromatographed (4:1 petroleum ether:ethyl acetate, silica) to providethe product as a white solid (6.07 g, 67%), m.p. 146°-147.5° C.

NMR (CDCl₃, 400 MHz): δ 1.54 (s, 9H, C(CH₃)₃), 4.00 (s, 3H, ArOCH₃),4.74 (broad s, 2H, NCH₂ CO₂), 6.84 (t, 2H, J=7.8 Hz, PhH), 6.94 (t, 1H,J=7.4 Hz, PhH), 7.28-7.35 (m, 4H, ArH and PhH), 7.58 (d, 1H, J=7.1 Hz,ArH), 8.00 (d, 1H, J=9 Hz, ArH), 8.35 (d, 1H, J=9.6 Hz, ArH).

IR (neat, cm⁻¹): 2998 (CH), 1746 (C═O), 1700 (C═O), 1663 (C═O), 1622 and1598 (C═C);

Anal. Calcd.: C, 64.06; H, 4.96; N, 2.87%.

Found: C, 63.86; H, 5.14; N, 2.96%.

Step 3. Preparation ofN-benzoyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycin

A solution ofN-benzoyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,1,1-dimethylethyl ester (6.03 g, 12.4 mmole) in trifluoroacetic acid (40mL) was stirred at room temperature for 10 minutes, then diluted withwater (600 mL) and extracted with ether (2×300 mL). The extracts werecombined, washed with saturated aqueous sodium chloride (1×100 mL),dried with magnesium sulfate, and the ether was removed. The resultantoil was suspended in water (300 mL) and the aqueous phase was slowlyneutralized to pH 5 with 10% aqueous sodium hydroxide solution. Theprecipitate was collected by suction filtration, washed with water (2×25mL), dried and flash chromatographed (9:1 chloroform:acetonitrile, 5%phosphoric acid in methanol treated silica). The solid was thenrecrystallized in 2:1 benzen:hexane to provide the product as whitecrystals (1.83 g, 33%), m.p. 143°-145° C. (dec.).

NMR (d⁶ DMSO, 400 MHz): δ 4.01 (s, 3H, ArOCH₃), 4.69 (broad s, 2H, NCH₂CO₂ H), 6.94 (t, 2H, J=7.5 Hz, PhH), 7.04 (t, 1H, J=6.9 Hz, PhH), 7.29(d, 2H, J=7.6 Hz, PhH), 7.47 (t, 1H, J=7.5 Hz, ArH), 7.61 (d, 1H, J=7.0Hz, ArH), 7.66 (d, 1H, J=9.6 Hz, ArH), 7.90 (broad d, 1H, J=8.7 Hz,ArH), 8.32 (d, 1H, J=9.6 Hz, ArH).

IR (KBr, cm-1): 1721 (C═O), 1708 (C═O), 1669 (C═O), 1622 and 1602 (C═C);

Anal. Calcd.: C, 61.26; H, 3.74; N, 3.25%.

Found: C, 61.06; H, 4.01; N, 3.53%.

EXAMPLE 11N-[(Dimethylamino)carbonyl]-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine[(I): R=N(CH₃)₂ ; R¹ =OCH₃ ; R² =CF₃ ; X=O] Step 1. Preparation ofN-[(dimethylamino)carbonyl]-6-methoxy-5-trifluoromethyl)-1-naphthalenecarboxamide

A suspension of 6-methoxy-5-(trifluoromethyl)-1-napthalenecarboxamide(20.0 g, 74.29 mmol) in dry THF (400 mL) was added to a stirredsuspension of sodium hydride (4.0 g, 1.12 eq of a 50% dispersion inmineral oil) in THF (200 mL) and the resulting suspension was stirredwas stirred at room temperature under a dry nitrogen atmosphere for 45minutes. A solution of N,N-dimethylcarbamoylchloride (6.8 mL, 1.0 eq) indry THF (100 mL) was added dropwise over a 20 minute period. After anadditional 45 minutes, saturated aqueous NH₄ Cl (200 mL) was added. Thereaction mixture was added to 350 mL of water, acidified with 10%aqueous HCl and filtered. The precipitate was placed in 2 L of water andbasified with 10% aqueous NaOH. This was filtered to remove the startingmaterial. The filtrate was acidified with 10% aqueous HC1 and filtered.This solid was washed with water and dried in vacuo to provide a whitesolid product (12.90 g, 51%), m.p. 169°-170.5° C.

NMR (d⁶ DMSO, 400 MHz): δ 2.46 (broad s, 6H, N(CH₃)₂), 4.01 (s, 3H,OCH₃), 7.59 (d, 1H, ArH), 7.66 (d, 1H, ArH), 7.70 (d, 1H, ArH), 8.15 (d,1H, ArH, 8.38 (d, 1H, ArH), 10.46 (s, 1H, NH).

IR (KBr, cm⁻¹): 3420, 3230 (NH), 1695, 1670 (C═O);

Anal. Calcd.: C, 56.47; H, 4.44; N, 8.23%.

Found: C, 56.14; H, 4.59; N, 8.25%.

Step 2. Preparation ofN-[(dimethylamino)carbonyl]-N-[[6-methoxy-5-(trifluoromethyl)-1-napthalenyl]carbonyl]glycine,1,1-dimethylethyl ester

Sodium hydride (1.90 g, 1.1 eq 50% dispersion in mineral oil) was addedto a stirred, cold (0°-10° C.) solution ofN-[(dimethylamino)carbonyl]-6-methoxy-5-(trifluormethyl)-1-naphthalenecarboxamide(11.9 g, 34.97 mmol) in dry DMF (65 mL). The solution was allowed towarm to room temperature for 20 minutes and was then recooled to 0°-10°C. t-Butyl bromoacetate (6.7 mL, 1.15 eq) was added and the reactionmixture was warmed to room temperature. After 45 minutes the reactionmixture was added to water (1 L) and the water was basified (with 10%NaOH) and extracted with ether (7×400 mL). The ether was washed withsaturated aqueous NaCl (700 mL) and dried (MgSO₄). The ether was removedto provide a white solid (12.2 g, 81%). A portion (2 g) wasrecrystallized from hexane to give a solid m.p. 117.5°-120° C.

NMR (d⁶ DMSO, 400 MHz): δ 1.46 (broad s, 9H, --C(CH₃)₃), 2.61 (broad s,6H, N(CH₃)₂), 4.01 (s, 3H, OCH₃), 4.33 (broad s, 2H, N--CH₂ --), 7.48(m, 1H, ArH), 7.66 (t, 1H, ArH), 7.73 (d, 1H, ArH), 8.16 (d, 1H, ArH),8.34 (m, 1H, ArH).

IR (KBr, cm⁻¹): 1730, 1685, 1650 (CONCO, CO₂ H).

Anal. Calcd.: C, 58.15; H, 5.54; N, 6.16%.

Found: C, 58.26; H, 5.66; N, 6.24%.

Step 3. Preparation ofN-[(dimethylamino)carbonyl]-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine

Trimethylsilyliodide (17.6 mL, 5.3 eq) was added to a stirred solutionof the ester (10.0 g, 23.23 mmol) in CCl₄ (130 mL) at room temperatureunder a dry N₂ atmosphere. After 2.5 hours the CCl₄ was removed andwater (500 mL) was added. The reaction mixture was acidified with 10% aqHCl and extracted with ethyl acetate (1×500 mL). The ethyl acetateextract was washed with dilute aqueous NaHSO₃ and dried (MgSO₄). Thesolvent was removed and the semisolid was triturated with 2:1benzene:hexane (450 mL) and then filtered. The solid was trituratedtwice more with benzene (100 mL) and filtered. The white solid was driedin vacuo (7.15 g, 77%), m.p. 145°-147° C.

NMR (d⁶ DMSO, 400 MHz): δ 2.62 (broad s, 6H, N(CH₃)₂), 4.02 (s, 3H,OCH₃), 4.37 (broad s, 2H, N--CH₂ --), 7.49 (m, 1H, ArH), 7.66 (t, 1H,ArH), 7.72 (d, 1H, ArH), 8.16 (m, 1H, ArH), 8.39 (m, 1H, ArH), 11.1 (m,1H, OH).

IR (KBR, cm⁻¹): 3650-2350 (CO₂ H), 1750, 1690, 1650 (CONCO, CO₂ H);

MS (m/e): 398 (3%), 309 (4%), 253 (100%);

Anal. Calcd.: C, 54.27; H, 4.30; N, 7.03%.

Found: C, 54.23; H, 4.49; N, 7.22%.

EXAMPLE 18N-[[6-Methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-[(methoxy)carbonyl]glycine[(I): R=OCH₃ ; R¹ =OCH₃ ; R² =CF₃ ; X=S] Step 1. Preparation ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]glycine,1,1-dimethylethyl ester

N-[[6-Methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,1,1-dimethylethyl ester, prepared by the process of Example 1, Step 1,(9.0 g, 23.4 mmol) was stirred in toluene (180 mL) at 20° C. Lawesson'sReagent,[2,4-bis(4-methoxypenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide](6.93g, 34.2 mmol) was added, and the mixture stirred at 20° C. for 16 hours,then at 60° C. for 4 hours. The mixture was cooled to 20° C., ethylacetate (450 mL), and water (500 mL) were added. The organic layer wasseparated, washed with brine (300 mL), dried (MgSO₄), filtered, andevaporated to yield the crude product which was chromatographed onsilica/5:1 hexanes:ethyl acetate to yield the product which ontrituration with hexanes yielded analytically pure material as whitesolid (7.0 g, 74.6%), m.p. 145°-146° C.

NMR (DMSO-d₆): δ 11.0 (s, 1H, NH), 8.50 (d, 1H, ArH), 8.10 (d, 1H, ArH),7.60-7.80 (m, 2H, ArH), 7.40 (d, 1H, ArH), 4.40 (d, 2H, CH₂), 4.0 (s,3H, OCH₃), 1.50 (s, 9H, C(CH₃)₃).

IR (KBr, cm⁻¹): 3310 (NH), 3000 (C--H), 1760, 1740, (C═O), 1620, 1660(C═C);

Calcd.: C, 57.13; H, 5.05; N, 3.51%.

Found: C, 57.35; H, 5.23; N, 3.59%.

Step 2. Preparation ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-(methoxycarbonyl)glycine,1,1-dimethylethyl ester

Solid sodium hydroxide (powered, 0.70 g, 17.5 mmol) was added to asolution ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]glycine,1,1-dimethylethyl ester (4.0 g, 10.0 mmol) in dry acetone (200 mL) at-40° C. over a dry ice-acetonitrile bath and the mixture was stirred at-40° C. for 30 minutes. Methyl chloroformate (0.80 mL, 10.9 mmol) wasadded, and the mixture allowed to warm to 20° C. over a 2 hour period,then stirred at 20° C. for an additional hour. The solvent wasevaporated and water (200 mL) added to the solid residue. Theprecipitated yellow solid was filtered, washed with water (3×100 mL),and petroleum ether (2×50 mL) to yield the product (3.6 g, 78.9%), m.p.114°-117° C.

NMR (CDCl₃): δ 8.35 (d, 1H, ArH), 8.15 (d, 1H, ArH), 7.25-7.50 (m, 3H,ArH), 5.10 (s, 2H, NCH₂), 4.0 (s, 3H, (OCH₃), 3.40 (s, 3H, COOCH₃), 1.50(s, 9H, C(CH₃)₃).

IR (KBr, cm⁻¹): 3310 (N--H), 3000 (C--H), 1760, 1740 (C═O), 1620, 1590(C═C).

Calcd.: C, 55.14; H, 4.85; N, 3.06%.

Found: C, 58.06; H, 5.23; N, 3.24%.

Step 3. Preparation ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-(methoxycarbonyl)glycine

Trifluoroacetic acid (5.0 mL, 64.9 mmol) was added to a solution ofN-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl-N-(methoxycarbonyl)-glycine,1,1-dimethylethyl ester (3.0 g, 6.5 mmol) in chloroform (25 mL) thenstirred at 20° C. for 6 hours. Chloroform (50 mL), and water (150 mL),were added and the organic layer was separated, washed with brine (200mL), dried (MgSO₄), filtered, and evaporated to yield an oil, which wasextracted with aqueous saturated sodium bicarbonate solution (200 mL),washed with ether (200 mL), and poured into 2 normal hydrochloric acid(80 mL). The aqueous solution was extracted with ether (200 mL), washedwith brine (3×100 mL), dried (MgSO₄), filtered, and evaporated to yieldan oil which crystallized on trituration with chloroform-petroleumether. The solid was recrystallized from chloroform-petroleum ether, andagain from ethyl acetate-hexanes to yield the pure product as a whitesolid (1.58 g, 65%), m.p. 160° C.

NMR (DMSO-d₆): δ 8.35 (d, 1H, ArH), 8.15 (d, 1H, ArH), 7.25-7.50 (m, 3H,ArH), 5.36 (s, 2H, NCH₂), 4.0 (s, 3H, OCH₃), 3.40 (s, 3H, COOCH₃).

IR (KBr, cm⁻¹): (3500-3400) COOH (broad), 1770, 1720 (C═O), 1620, 1590(C═C);

Calcd.: C, 50.87; H, 3.52; N, 3.49%.

Found: C, 51.11; H, 3.91; H, 3.87%.

We claim:
 1. A compound of formula (I) ##STR18## wherein R is hydrogen,lower alkyl containing 1 to 3 carbon atoms, lower alkoxy containing 1 to6 carbon atoms, trifluoroethoxy, phenyl, benzyloxy, chloro-ornitro-substituted benzyloxy, or dimethylamino; R¹ is hydrogen or loweralkoxy containing 1 to 3 carbon atoms; R² is halogen or lowerperfluoralkyl containing 1 to 3 carbon atoms; X is oxygen or sulfur, orthe pharmaceutically acceptable salts thereof.
 2. The compoundsaccording to claim 1 having the structure of formula (II) ##STR19##wherein R is hydrogen, lower alkyl containing 1 to 3 carbon atoms, loweralkoxy containing 1 to 6 carbon atoms, trifluoroethoxy, phenyl,benzyloxy, chloro-or nitro-substituted benzyloxy, or dimethylamino; R¹is hydrogen or lower alkoxy containing 1 to 3 carbon atoms; R² ishalogen or lower perfluoroalkyl containing 1 to 3 carbon atoms, or thepharmaceutically acceptable salts thereof.
 3. The compounds according toclaim 2 having the structure of formula (III) ##STR20## wherein R ishydrogen or alkoxy wherein alkoxy contains 1 to 6 carbon atoms, and thepharmaceutically acceptable salts thereof.
 4. The compound according toclaim 3 designatedN-(ethoxycarbonyl)-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,and the pharmaceutically acceptable salts thereof.
 5. The compoundaccording to claim 3 designatedN-(methoxycarbonyl)-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,and the pharmaceutically acceptable salts thereof.
 6. The compoundaccording to claim 3 designatedN-formyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine,and the pharmaceutically acceptable salts thereof.
 7. A pharmaceuticalcomposition for preventing or relieving neuropathy, nephropathy,retinopathy, or cataracts in a diabetic mammal, which comprises analleviating or prophylactic amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 8. A method of preventing orrelieving neuropathy, nephropathy, retinopathy, or cataracts in adiabetic mammal, which comprises administering to said mammal analleviating or prophylactic amount of a compound of claim
 1. 9. A methodof preventing or relieving neuropathy, nephropathy, retinopathy, orcataracts in a diabetic mammal, which comprises administering to saidmammal an alleviating or prophylactic amount of a compound of claim 1 inconjunction with insulin or an oral hypoglycemic agent.